2-Aminophenoxazine-3-one Suppresses the Growth of Mouse Malignant Melanoma B16 Cells Transplanted into C57BL/6Cr Slc Mice

Miyano-Kurosaki, Naoko; Kurosaki, Kunihiko; Hayashi, Michiko; Takaku, Hiroshi; Hayafune, Masaaki; Shirato, Ken; Kasuga, Teruhiko; Endo, Takahiko; Tomoda, Akio

doi:10.1248/bpb.29.2197

Cited by 25 publications

(38 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that 3 inhibits the proliferation of mouse 282 malignant melanoma B16 cells in vitro, prevents the growth of melanoma cells transplanted into mice in vivo at extremely low concentrations, and causes only a few adverse effects on mice in contrast to 4 [22]. The synthetic aminophenoxazinone compound 2-amino-4,4a -dihydro4a,7-dimethyl-2H-phenoxazin-3-one (5) was found to be a potent inhibitor of proliferation and an inducer of apoptosis in all leukemia cell lines showing few adverse effects in vivo [23].…”

Section: Discussionmentioning

confidence: 99%

Elloxazinones A and B, New Aminophenoxazinones from Streptomyces griseus Acta 2871†

et al. 2007

View full text Add to dashboard Cite

Two new aminophenoxazinone compounds with antitumor activity, elloxazinone A and B, were isolated from the culture filtrate of Streptomyces griseus Acta 2871. Their chemical structures were determined by mass spectrometry, NMR spectroscopy and X-ray analysis. Elloxazinones A and B showed a moderate inhibition of the proliferation of human cells from gastric adenocarcinoma in vitro but a strong inhibition of hepatocellular carcinoma cells whereas elloxazinone B strongly inhibited the proliferation of human breast carcinoma cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Elloxazinones A and B, New Aminophenoxazinones from Streptomyces griseus Acta 2871†

et al. 2007

View full text Add to dashboard Cite

show abstract

“…3). Phx-3 has been found to exert less adverse effects on mice (23). Therefore, Phx-3 may be a potential candidate for treating lung cancer in the future.…”

Section: Discussionmentioning

confidence: 99%

“…Phenoxazine compounds including 2-amino-4, 4·-dihydro-·, 7-dimethyl-3H-phenoxazine-3-one (Phx-1), and 2-aminophenoxazine-3-one (Phx-3), which are synthesized by the reactions of o-aminophenols with bovine hemoglobin (18,19), are oxidative phenoxazines like actinomycin D (20) and exert anticancer activity against various cancer cells in vitro and in vivo, promoting cellular apoptosis (21)(22)(23) 2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells caspase-dependent apoptosis in multiple myeloma cells (24), and caspase-independent apoptosis in neuroblastoma cells, glioma cells and gastric cancer cells (25)(26)(27). However, it remains unclear how pHi is affected, and how ROS and NF-κB are implicated in the apoptosis of cancer cells in the presence of Phx-3.…”

Section: Introductionmentioning

confidence: 99%

2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells

Tomoda¹

2010

Int J Oncol

View full text Add to dashboard Cite

Abstract. 2-Aminophenoxazine-3-one (Phx-3)-induced apoptosis was investigated. Phx-3 suppressed the viability of human lung adenocarcinoma cell line A549 and induced cellular apoptosis 6 h after treatment. Prior to these events, intracellular pH (pHi) was rapidly decreased from pH 7.65 to 7.10 within 30 min when A549 cells were treated with 7 μM Phx-3. This intracellular acidification continued for 3 h in the cells. Augmented production of reactive oxygen species (ROS) was obseved 1 h after treatment of A549 cells with 7 μM Phx-3, and cell cycle arrest at G 1 was indicated 3 h after treatment. The translocation of NF-κB from the cytosol to the nucleus was clearly indicated 1 h after the administration of Phx-3 to A549 cells, while it was significantly suppressed when Nac, a scavenger of ROS, was added to the cells with Phx-3. The Phx-3-induced apoptosis in A549 cells was significantly suppressed when Nac was administered to the cells. These results suggest that a decrease of pHi, caused by depolarization of the mitochondria, may trigger the dysfunction of mitochondria causing ROS production; therefore, both the translocation of NF-κB from the cytoplasm to the nucleus and apoptosis induction were promoted in A549 cells. Microscopic examination of the cellular localization of Phx-3 in A549 cells revealed that Phx-3 was mainly localized in the cytoplasm and the mitochondria, but not in the nucleus. The present results indicate that Phx-3 might be a strong anticancer drug against lung cancer, which is intractable to chemotherapy, by causing various early events, including the decrease of pHi and ROS production, and finally inducing cellular apoptosis.

show abstract

“…Simultaneous induction of differentiation and apoptosis by Phx-3 was also reported in malignant melanoma G-361 cells, which produced melanin and induced nuclear chromatin condensation and DNA fragments in response to . In vivo experiments demonstrated that Phx-3 prevented pulmonary metastasis of mouse B16 melanoma cells (13). In addition to anti-cancer activity, Phx-3 exhibits various biological activities, including a potent anti-inflammatory effect by suppressing the production of nitric oxide (NO) and prostaglandin E2 (14), as well as immunosuppressive, anti-viral and anti-mycobacterial effects and the elimination of Helicobacter pylori (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Involvement of endoplasmic reticulum stress-mediated CHOP (GADD153) induction in the cytotoxicity of 2-aminophenoxazine-3-one in cancer cells

Moriya

Miyazawa

Kawaguchi³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

Abstract. In this study, 2-aminophenoxazine-3-one (Phx-3) exhibited a potent cell growth inhibitory effect with apoptotic features in a dose-dependent manner in various cancer cell lines tested. Comparison of the expression profiles of endoplasmic reticulum (ER) stress-related genes in U266 multiple myeloma cells after treatment with Phx-3 and the ER stress inducers tunicamycin (TNM) and thapsigargin (TPG) indicated that although TNM and TPG potently induced pro-apoptotic transcription factor CHOP (GADD153) within 8 h of treatment, Phx-3 induced almost no CHOP within 48 h of treatment in U266 cells. However, murine embryonic fibroblast (MEF) cells and other cancer cell lines (e.g. A549 lung cancer cells and HL-60 acute leukemia cells) exhibited up-regulation of CHOP after treatment with Phx-3. The potency of CHOP induction in response to Phx-3 appeared to be partially correlated with the cytotoxic sensitivity of Phx-3 among various cell lines tested. MEF cells derived from CHOP knockout mice were more resistant to Phx-3 than wild-type MEF cells. Since Phx-3 has been shown to induce activation of NF-κB, a transcription factor functioning as a repressor of CHOP, we further treated U266 cells with a combination of Phx-3 and NF-κB inhibitors (e.g. BAY11-7082 or parthenolide). This enhanced cytotoxicity along with up-modulation of CHOP in U266 cells. These data suggest that ER stress-mediated CHOP induction by Phx-3 is involved in the cytotoxic effect. Regulation of CHOP expression appears to be a potent therapeutic target for cancer treatment.

show abstract

2-Aminophenoxazine-3-one Suppresses the Growth of Mouse Malignant Melanoma B16 Cells Transplanted into C57BL/6Cr Slc Mice

Cited by 25 publications

References 15 publications

Elloxazinones A and B, New Aminophenoxazinones from Streptomyces griseus Acta 2871†

Elloxazinones A and B, New Aminophenoxazinones from Streptomyces griseus Acta 2871†

2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells

Involvement of endoplasmic reticulum stress-mediated CHOP (GADD153) induction in the cytotoxicity of 2-aminophenoxazine-3-one in cancer cells

Contact Info

Product

Resources

About